Deficiency of the Two-Pore-Domain Potassium Channel TREK-1 Promotes Hyperoxia-Induced Lung Injury

Abstract

Objective We previously reported the expression of the 2-pore domain K+ channel TREK-1 in lung epithelial cells and proposed a role for this channel in the regulation of alveolar epithelial cytokine secretion. In this study we focused on investigating the role of TREK-1 in vivo in the development of hyperoxia-induced lung injury. Design Laboratory animal experiments. Setting University research laboratory. Subjects Wild type and TREK-1 deficient mice. Interventions Mice were anesthetized and exposed to 1) room air, no mechanical ventilation, 2) 95% hyperoxia for 24 hours, 3) 95% hyperoxia for 24 hours followed by mechanical ventilation for 4 hours. Measurements and Main Results Hyperoxia exposure accentuated lung injury in TREK-1 deficient mice but not controls, resulting in increased in Lung Injury Scores (LIS), broncho-alveolar lavage (BAL) fluid cell numbers and cellular apoptosis, and a decrease in quasi-static lung compliance. Exposure to a combination of hyperoxia and injurious mechanical ventilation resulted in further morphological lung damage, increased LIS and BAL fluid cell numbers in control but not TREK-1 deficient mice. At baseline and after hyperoxia exposure BAL cytokine levels were unchanged in TREK-1 deficient mice compared to controls. Exposure to hyperoxia and mechanical ventilation resulted in an increase in BAL IL-6, MCP-1 and TNF-α levels in both mouse types, but the increase in IL-6 and MCP-1 levels was less prominent in TREK-1 deficient mice than in controls. Lung tissue MIP-2, KC and IL-1β gene expression was not altered by hyperoxia in TREK-1 deficient mice compared to controls. Furthermore, we show for the first time TREK-1 expression on alveolar macrophages and unimpaired TNF-α secretion from TREK-1 deficient macrophages. Conclusion TREK-1 deficiency resulted in increased sensitivity of lungs to hyperoxia but this effect is less prominent if overwhelming injury is induced by the combination of hyperoxia and injurious mechanical ventilation. TREK-1 may constitute a new potential target for the development of novel treatment strategies against hyperoxia-induced lung injury.

Trek1 contributes to maintaining nasal epithelial barrier integrity

“…However, inverse results were also observed by Schwingshackl et al that combination of hyperoxia and injurious mechanical ventilation resulted in further morphological lung damage in controls but not Trek1-deficient mice 36 . The fact implicates that the role of Trek1 in modulating the epithelial barrier functions is dependent on the nature of stimuli; further studies are needed to elucidate the underlying mechanisms.…”

“…It is also reported that that Trek-1 deficiency has been shown to cause significant alterations in inflammatory cytokine secretion (IL-6, MCP-1, RANTES) from lung epithelial cells 36,37 . Although we utilized a different disease model in the present study, comparing with Schwingshacle's work, we have revealed another aspect of Trek1's properties that the expression of Trek1 can be suppressed by Th2 cytokines in the nasal epithelia.…”

The role of stretch-activated ion channels in acute respiratory distress syndrome: finally a new target?

“…Based on these in vitro findings we expected that TREK-1 ko mice would be protected from HO-and MV-induced lung injury. To our surprise, however, exposure of TREK-1 ko mice to HO increases lung injury as evidenced by gross lung anatomy, hematoxylin and eosin staining of lung sections (increased inflammatory cell infiltration and hemorrhage), increased lung injury scores, decreased lung compliance, and increased macrophage and neutrophil accumulation in the BAL fluid of TREK-1 ko mice (174). Interestingly, exposure of these mice to HOϩMV results in no further injury when compared with HO exposure alone.…”

“…This is only one example of a well-defined pathway in rodents that, if confirmed in the human lung, could become tremendously useful in designing new therapies against ARDS. Other exciting candidates are so-called 2-pore domain K ϩ channels (K2P), which are not only stretch sensitive (73,223) but are also regulated by HO (172) and affect cytokine secretion from mouse ARDS lungs (174). We are now finally at a stage where many of the characteristics assigned to individual SACs can be exploited in the context of ventilator-induced lung injury (VILI), which allows us to specifically target these channels as new therapeutic options against ARDS.…”

“…This is further evidenced by the fact that, besides the introduction of "lung-protective," low tidal volume ventilation strategies and possibly prone positioning, few if any interventions have improved the outcomes or survival rates of ARDS patients over the past two decades (16,51). Importantly, in tissues other than the lung, SACs are well known to function as so-called "signal integrators" and it is becoming increasingly evident that in the lung these channels could constitute the link between HO, MV, and cytokine effects (76,166,174).…”